CD2AP is an 80 KD protein that was cloned as a protein involved in T cell activation. CD2AP also plays a major role in the kidney. CD2AP knockout mice are born with congenital nephritic syndrome and CD2AP is expressed in the glomerular epithelial cell or podocyte. Our previous work suggests that CD2AP plays a critical role in maintaining the integrity of the slit diaphragm, a structure that is critical in the glomerular filtration apparatus. Recently, we discovered that our CD2AP heterozygous mice demonstrate an increased susceptibility to renal injury caused by nephrotoxic antibodies or when bred to the NZB mouse. This suggested that CD2AP heterozygosity might play a role in human glomerular disease. In our preliminary work, we have identified human patients with the diagnosis of focal segmental glomerulosclerosis who are heterozygous for CD2AP. In this grant application, we propose to extend these studies by analyzing a larger population of patients with FSGS for mutations in CD2AP. In the first two aims, we propose to identify genetic variants of CD2AP and determine their prevalence in the population. In aim #3, we propose a series of experiments to determine whether these mutations are disease causing, by testing mutated forms of CD2AP biochemically, by their ability to reconstitute function after transfection in CD2AP deficient cell lines and by their ability to rescue the renal phenotype of the knockout mouse. We hope that these studies lead to new insights into diseases of the glomerulus.